The major objectives of this research proposal are (1) to study erythropoietin physiology in the mammalian fetus and (2) to study the influence of erythropoietic inhibitory factors and stimulators on disturbances of red cell production in humans. In the first part of the study, we will define the role of erythropoietin in the control of fetal erythropoiesis by in vivo studies in the fetal goats and sheep. The influence of maternal and fetal anemia and polycythemia on this regulation will be examined. Sites of erythropoietin production in the fetus will be established by organ removal techniques. Transplacental kinetics of hormonal (erythropoietin) transfer will be measured by the induction of endogenous and infusion of exogenous erythropoietin. Our second major objective is to study the physiology of erythropoietin control in red cell disorders of man-especially polycythemia vera and pure red cell aplasia. In both disorders we will identify both stimulatory and inhibitory factors by special in vivo and in vitro techniques. We shall examine current concepts concerning the biogenesis of erythropoietin by appropriate studies of precursor factors in man.